Journal
CANCER LETTERS
Volume 437, Issue -, Pages 89-99Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.08.026
Keywords
CAFs; FXR Tumor microenvironment; Breast cancer; Nuclear receptors
Categories
Funding
- My First AIRC Grant (MFAG) [16899]
- National Research, Development and Innovation Office, Hungary [NVKP_16-1-2016-0037]
- FIRC Grant [16487]
- AIRC [18602]
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Cancer-associated Fibroblasts (CAFs), the principal components of tumor microenvironment, play multiple role in breast cancer progression. We have previously shown an oncosuppressive role of the nuclear Farnesoid X Receptor (FXR) in mammary epithelial cancer cells, here we assessed whether FXR activation may affect CAF tumor-promoting features. We showed that FXR is expressed in human CAFs isolated from four patients and treatment with the selective FXR agonist GW4064 decreased CAF migration, stress-fiber formation and contractility. RNA-sequencing highlighted cell movement and pathways known to govern cell cytoskeleton organization and migration among the most down-regulated functions and ingenuity canonical pathways upon GW4064 treatment. FXR activation reduced expression of different secreted factors. Coculture experiments revealed a reduced growth and motility of breast cancer cells treated with conditioned-media derived from GW4064-treated CAFs. Increased FXR levels in bulk tumors correlated with a longer patient survival. Our results evidence that FXR activation inhibits tumor-stimulatory activities of CAFs by impacting their mechanical properties and their paracrine signaling repertoire, suggesting that nuclear FXR ligands, by targeting both neoplastic cells and supportive stroma, may represent a promising avenue for the future management of breast cancer.
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